肠道菌群影响慢性乙型肝炎、慢性丙型肝炎及相关肝病的研究进展

邓辉; 张斌; 朱彬; 迪丽胡玛尔·扎依尔; 王伟仙; 郭春霞; 杨东亮; 郑昕; 王俊忠; 王宝菊

doi:10.3969/j.issn.1001-5256.2022.05.035

肠道菌群影响慢性乙型肝炎、慢性丙型肝炎及相关肝病的研究进展

DOI: 10.3969/j.issn.1001-5256.2022.05.035

华中科技大学同济医学院附属协和医院感染性疾病科，武汉 430022

基金项目:

国家传染病科技重大专项课题 (2017ZX10304402-002-00)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：邓辉起草文章内容; 张斌、朱彬、迪丽胡玛尔·扎依尔、王伟仙、郭春霞、杨东亮、郑昕、王俊忠参与文章框架设计与修改文章; 王宝菊提供思路与框架，修改并校对文章。

详细信息

通信作者:
王宝菊，bjwang73@163.com

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出版历程
- 收稿日期: 2021-12-28
- 出版日期: 2022-05-20

Research advances in the role of gut microbiota in chronic hepatitis B, chronic hepatitis C, and related liver diseases

Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

Research funding:

National Science and Technology Major Project for Infectious Diseases of China (2017ZX10304402-002-00)

More Information

Corresponding author: WANG Baoju, bjwang73@163.com(ORCID: 0000-0001-6942-570X)

摘要

摘要: HBV、HCV感染常可进展为肝硬化、肝衰竭和肝细胞癌等终末期肝病，危及患者生命。近年来研究发现肠道菌群与慢性病毒性肝病关系密切。本文就肠道菌群与慢性乙型肝炎、慢性丙型肝炎及其相关肝病之间的相关性，以及靶向肠道菌群治疗慢性乙型肝炎及其相关肝病的研究进展进行了综述，以期为临床治疗慢性乙型肝炎、慢性丙型肝炎及其相关肝病提供更多思考。
- 肝炎病毒 /
- 胃肠道微生物组 /
- 肝硬化 /
- 肝功能衰竭 /
- 治疗学
Abstract: Hepatitis B virus infection and hepatitis C virus infection often progress to end-stage liver diseases such as liver cirrhosis, liver failure, and hepatocellular carcinoma, which endanger the life of patients. Recent studies have shown that gut microbiota are closely associated with chronic viral liver diseases. This article reviews the association of gut microbiota with chronic hepatitis B (CHB), chronic hepatitis C (CHC), and their related liver diseases and the research advances in therapies targeting gut microbiota against CHB and its related liver diseases, in order to provide more ideas for the clinical treatment of CHB, CHC, and their related liver diseases.
- Hepatitis Viruses /
- Gastrointestinal Microbiome /
- Liver Cirrhosis /
- Liver Failure /
- Therapeutics

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图 1 肠道菌群与慢性病毒性肝病

注：①肠道菌群参与慢性病毒性肝炎病情进展; ②靶向肠道菌群用于治疗慢性病毒性肝炎及其相关肝病。

Figure 1. The relationship of gut microbiota and chronic viral liver diseases

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参考文献(49)

[1]	EL-SERAG HB. Epidemiology of viral hepatitis and hepatocellular carcinoma[J]. Gastroenterology, 2012, 142(6): 1264-1273. e1. DOI: 10.1053/j.gastro.2011.12.061.
[2]	MILOSEVIC I, VUJOVIC A, BARAC A, et al. Gut-liver axis, gut microbiota, and its modulation in the management of liver diseases: A review of the literature[J]. Int J Mol Sci, 2019, 20(2): 395. DOI: 10.3390/ijms20020395.
[3]	LEY RE, PETERSON DA, GORDON JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine[J]. Cell, 2006, 124(4): 837-848. DOI: 10.1016/j.cell.2006.02.017.
[4]	UBEDA C, DJUKOVIC A, ISAAC S. Roles of the intestinal microbiota in pathogen protection[J]. Clin Transl Immunology, 2017, 6(2): e128. DOI: 10.1038/cti.2017.2.
[5]	WHO. World Health Organization Fact Sheet[EB/OL]. [2022-02-12]. https://www.who.int/news-room/fact-sheets/detail/hepatitis-b, 2021.
[6]	LIU J, LIANG W, JING W, et al. Countdown to 2030: eliminating hepatitis B disease, China[J]. Bull World Health Organ, 2019, 97(3): 230-238. DOI: 10.2471/BLT.18.219469.
[7]	WANG J, WANG Y, ZHANG X, et al. Gut microbial dysbiosis is associated with altered hepatic functions and serum metabolites in chronic hepatitis B patients[J]. Front Microbiol, 2017, 8: 2222. DOI: 10.3389/fmicb.2017.02222.
[8]	ZENG Y, CHEN S, FU Y, et al. Gut microbiota dysbiosis in patients with hepatitis B virus-induced chronic liver disease covering chronic hepatitis, liver cirrhosis and hepatocellular carcinoma[J]. J Viral Hepat, 2020, 27(2): 143-155. DOI: 10.1111/jvh.13216.
[9]	ZHU Q, XIA P, ZHOU X, et al. Hepatitis B virus infection alters gut microbiota composition in mice[J]. Front Cell Infect Microbiol, 2019, 9: 377. DOI: 10.3389/fcimb.2019.00377.
[10]	CHOU HH, CHIEN WH, WU LL, et al. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota[J]. Proc Natl Acad Sci U S A, 2015, 112(7): 2175-2180. DOI: 10.1073/pnas.1424775112.
[11]	CHEN Z, XIE Y, ZHOU F, et al. Featured gut microbiomes associated with the progression of chronic hepatitis B disease[J]. Front Microbiol, 2020, 11: 383. DOI: 10.3389/fmicb.2020.00383.
[12]	GEHRING AJ, PROTZER U. Targeting innate and adaptive immune responses to cure chronic HBV infection[J]. Gastroenterology, 2019, 156(2): 325-337. DOI: 10.1053/j.gastro.2018.10.032.
[13]	GUO W, ZHOU X, LI X, et al. Depletion of gut microbiota impairs gut barrier function and antiviral immune defense in the liver[J]. Front Immunol, 2021, 12: 636803. DOI: 10.3389/fimmu.2021.636803.
[14]	URDANETA V, CASADESÚS J. Interactions between bacteria and bile salts in the gastrointestinal and hepatobiliary tracts[J]. Front Med (Lausanne), 2017, 4: 163. DOI: 10.3389/fmed.2017.00163.
[15]	SAYIN SI, WAHLSTRÖM A, FELIN J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist[J]. Cell Metab, 2013, 17(2): 225-235. DOI: 10.1016/j.cmet.2013.01.003.
[16]	WANG X, CHEN L, WANG H, et al. Modulation of bile acid profile by gut microbiota in chronic hepatitis B[J]. J Cell Mol Med, 2020, 24(4): 2573-2581. DOI: 10.1111/jcmm.14951.
[17]	KOH A, de VADDER F, KOVATCHEVA-DATCHARY P, et al. From dietary fiber to host physiology: Short-chain fatty acids as key bacterial metabolites[J]. Cell, 2016, 165(6): 1332-1345. DOI: 10.1016/j.cell.2016.05.041.
[18]	BAJAJ JS, REDDY KR, O'LEARY JG, et al. Serum levels of metabolites produced by intestinal microbes and lipid moieties independently associated with acute-on-chronic liver failure and death in patients with cirrhosis[J]. Gastroenterology, 2020, 159(5): 1715-1730. e12. DOI: 10.1053/j.gastro.2020.07.019.
[19]	WHO. World Health Organization Fact Sheet[EB/OL]. [2022-02-12]https://www.who.int/news-room/fact-sheets/detail/hepatitis-c, 2021.
[20]	INOUE T, NAKAYAMA J, MORIYA K, et al. Gut dysbiosis associated with hepatitis C virus infection[J]. Clin Infect Dis, 2018, 67(6): 869-877. DOI: 10.1093/cid/ciy205.
[21]	WELLHÖNER F, DÖSCHER N, WOELFL F, et al. Eradication of chronic HCV infection: Improvement of dysbiosis only in patients without liver cirrhosis[J]. Hepatology, 2021, 74(1): 72-82. DOI: 10.1002/hep.31700.
[22]	PÉREZ-MATUTE P, ÍÑIGUEZ M, VILLANUEVA-MILLÁN MJ, et al. Short-term effects of direct-acting antiviral agents on inflammation and gut microbiota in hepatitis C-infected patients[J]. Eur J Intern Med, 2019, 67: 47-58. DOI: 10.1016/j.ejim.2019.06.005.
[23]	PONZIANI FR, PUTIGNANI L, PARONI STERBINI F, et al. Influence of hepatitis C virus eradication with direct-acting antivirals on the gut microbiota in patients with cirrhosis[J]. Aliment Pharmacol Ther, 2018, 48(11-12): 1301-1311. DOI: 10.1111/apt.15004.
[24]	SULTAN S, EL-MOWAFY M, ELGAML A, et al. Alterations of the treatment-naive gut microbiome in newly diagnosed hepatitis C virus infection[J]. ACS Infect Dis, 2021, 7(5): 1059-1068. DOI: 10.1021/acsinfecdis.0c00432.
[25]	SARIN SK, CHOUDHURY A, SHARMA MK, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): An update[J]. Hepatol Int, 2019, 13(4): 353-390. DOI: 10.1007/s12072-019-09946-3.
[26]	LI L, WU Z, MA W, et al. Changes in intestinal microflora in patients with chronic severe hepatitis[J]. Chin Med J (Engl), 2001, 114(8): 869-872.
[27]	YAO X, YU H, FAN G, et al. Impact of the gut microbiome on the progression of hepatitis B virus related acute-on-chronic liver failure[J]. Front Cell Infect Microbiol, 2021, 11: 573923. DOI: 10.3389/fcimb.2021.573923.
[28]	WANG K, ZHANG Z, MO ZS, et al. Gut microbiota as prognosis markers for patients with HBV-related acute-on-chronic liver failure[J]. Gut Microbes, 2021, 13(1): 1-15. DOI: 10.1080/19490976.2021.1921925.
[29]	DUPONT HL. Review article: the antimicrobial effects of rifaximin on the gut microbiota[J]. Aliment Pharmacol Ther, 2016, 43 (Suppl 1): 3-10. DOI: 10.1111/apt.13434.
[30]	SHARMA BC, SHARMA P, LUNIA MK, et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy[J]. Am J Gastroenterol, 2013, 108(9): 1458-1463. DOI: 10.1038/ajg.2013.219.
[31]	KANG SH, LEE YB, LEE JH, et al. Rifaximin treatment is associated with reduced risk of cirrhotic complications and prolonged overall survival in patients experiencing hepatic encephalopathy[J]. Aliment Pharmacol Ther, 2017, 46(9): 845-855. DOI: 10.1111/apt.14275.
[32]	GOEL A, RAHIM U, NGUYEN LH, et al. Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis[J]. Aliment Pharmacol Ther, 2017, 46(11-12): 1029-1036. DOI: 10.1111/apt.14361.
[33]	BAJAJ JS. Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis[J]. Aliment Pharmacol Ther, 2016, 43 (Suppl 1): 11-26. DOI: 10.1111/apt.13435.
[34]	BAJAJ JS, HEUMAN DM, SANYAL AJ, et al. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy[J]. PLoS One, 2013, 8(4): e60042. DOI: 10.1371/journal.pone.0060042.
[35]	CHAUHAN A, KUMAR R, SHARMA S, et al. Fecal microbiota transplantation in hepatitis B e antigen-positive chronic hepatitis B patients: A pilot study[J]. Dig Dis Sci, 2021, 66(3): 873-880. DOI: 10.1007/s10620-020-06246-x.
[36]	REN YD, YE ZS, YANG LZ, et al. Fecal microbiota transplantation induces hepatitis B virus e-antigen (HBeAg) clearance in patients with positive HBeAg after long-term antiviral therapy[J]. Hepatology, 2017, 65(5): 1765-1768. DOI: 10.1002/hep.29008.
[37]	BAJAJ JS, KASSAM Z, FAGAN A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial[J]. Hepatology, 2017, 66(6): 1727-1738. DOI: 10.1002/hep.29306.
[38]	BAJAJ JS, SALZMAN N, ACHARYA C, et al. Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis[J]. JCI Insight, 2019, 4(24) : e133410. DOI: 10.1172/jci.insight.133410.
[39]	DEFILIPP Z, BLOOM PP, TORRES SOTO M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant[J]. N Engl J Med, 2019, 381(21): 2043-2050. DOI: 10.1056/NEJMoa1910437.
[40]	Chinese Society of Hepatology, Chinese Medical Association. Guidelines on the management of hepatic encephalopathy in cirrhosis[J]. J Clin Hepatol, 2018, 34(10): 2076-2089. DOI: 10.3969/j.issn.1001-5256.2018.10.007. 中华医学会肝病学分会. 肝硬化肝性脑病诊疗指南[J]. 临床肝胆病杂志, 2018, 34(10): 2076-2089. DOI: 10.3969/j.issn.1001-5256.2018.10.007.
[41]	ZHENG N, YU LL, CAO Z. Effect of treatment with viable bifidobacterium quadruple on liver function, cytokines and intestinal flora in patients with liver cirrhosis[J]. Med & Pharm J Chin PLA, 2020, 32(8): 36-39. DOI: 10.3969/j.issn.2095-140X.2020.08.009. 郑能, 于力力, 曹志. 双歧杆菌四联活菌治疗对肝硬化患者肝功能、细胞因子及肠道菌群的影响[J]. 解放军医药杂志, 2020, 32(8): 36-39. DOI: 10.3969/j.issn.2095-140X.2020.08.009.
[42]	DHIMAN RK, RANA B, AGRAWAL S, et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial[J]. Gastroenterology, 2014, 147(6): 1327-1337. e3. DOI: 10.1053/j.gastro.2014.08.031.
[43]	XIA X, CHEN J, XIA J, et al. Role of probiotics in the treatment of minimal hepatic encephalopathy in patients with HBV-induced liver cirrhosis[J]. J Int Med Res, 2018, 46(9): 3596-3604. DOI: 10.1177/0300060518776064.
[44]	Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Guideline for diagnosis and treatment of liver failure(2018)[J]. J Clin Hepatol, 2019, 35(1): 38-44. DOI: 10.3969/j.issn.1001-5256.2019.01.007. 中华医学会感染病学分会肝衰竭与人工肝学组, 中华医学会肝病学分会重型肝病与人工肝学组. 肝衰竭诊治指南(2018年版)[J]. 临床肝胆病杂志, 2019, 35(1): 38-44. DOI: 10.3969/j.issn.1001-5256.2019.01.007.
[45]	YAN H, PENG B, LIU Y, et al. Viral entry of hepatitis B and D viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide[J]. J Virol, 2014, 88(6): 3273-3284. DOI: 10.1128/JVI.03478-13.
[46]	MOUZANNAR K, FUSIL F, LACOMBE B, et al. Farnesoid X receptor-α is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo[J]. FASEB J, 2019, 33(2): 2472-2483. DOI: 10.1096/fj.201801181R.
[47]	ZHANG DY, ZHU L, LIU HN, et al. The protective effect and mechanism of the FXR agonist obeticholic acid via targeting gut microbiota in non-alcoholic fatty liver disease[J]. Drug Des Devel Ther, 2019, 13: 2249-2270. DOI: 10.2147/DDDT.S207277.
[48]	FRIEDMAN ES, LI Y, SHEN TD, et al. FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid[J]. Gastroenterology, 2018, 155(6): 1741-1752. e5. DOI: 10.1053/j.gastro.2018.08.022.
[49]	MARKHAM A, KEAM SJ. Obeticholic acid: First global approval[J]. Drugs, 2016, 76(12): 1221-1226. DOI: 10.1007/s40265-016-0616-x.